Master of Science
Luyt, Len G.
Aberrant function and over-expression of protease-activated receptor 2 (PAR2), a GPCR, is associated with various cancers and inflammatory diseases. PAR2-targeting ligands have been developed with therapeutic applications but the development of imaging probes is lacking. A series of PAR2-targeted fluorescent and 18F-PET imaging agents were synthesized and assessed for PAR2-binding. A novel dye-conjugated peptide, Isox-Cha-Chg-ARK(Sulfo-Cy5)-NH2 (EC50=16nM, KD=38nM), showed >10-fold increase in potency and binding affinity for PAR2 compared to the leading known fluorescent probe. A novel PET imaging 18F-labeled peptide, Isox-Cha-Chg-AR-Dpr([18F]4-FB)-NH2, is the first PAR2-targeted in vivo imaging agent. It showed significant uptake in PAR2-expressing prostate cancer cells compared to controls (P19F-standard was highly potent (EC50=13nM) and PAR2-selective. The peptide was 18F-labeled through standard prosthetic group labeling (RCY=37±3%, RCP>98%, Am=20±2GBq/µmol, EOS=125±2min, n=4). These probes are useful chemical tools that could provide insight into PAR2 expression in vitro and in vivo with potential clinical applications in PAR2-related diseases.
LeSarge, Jordan C., "Design, Synthesis, and Evaluation of Novel Protease-Activated Receptor 2 (PAR2)-Targeting Imaging Agents for Cancer" (2018). Electronic Thesis and Dissertation Repository. 5533.